At least seven different receptor classes mediate the physiological activities attributed to the participation of the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT for short). These receptor classes are designated as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 according to an internationally recognized classification system. Most of these classes include further distinguishable receptor subtypes; thus, the 5-HT1 class includes receptors which in turn may be divided into at least five subclasses, designated 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1E (Boess, Martin; Neuropharmacology 33:275-317 (1994)).
The properties, function, and pharmacology of these receptor subtypes have been summarized, for example, by: (a) Kennet G. A., “Serotonin Receptors and Their Function,” TOCRIS Review (http://www.tocris.com/serotonin.htm), published May 1997; and (b) Peroutka, S. J., 1994, “Molecular Biology of Serotonin (5-HT) Receptors,” Synapse 18, 241-260 and Current Drug Targets—CNS & Neurological Disorders 2004, 3, Issue 1.
The 5-HT5 class was first described by Plassat et al., The EMBO Journal, Vol. 11, No. 13, PP. 4779-4786 (1992). A distinction is made between 5-HT5A and 5-HT5B receptors (Erlander et al., Proc. Natl. Acad. Sci. USA 90:3452-3456 (1993)). Although only slight sequence homologies exist between 5-HT5 receptors and other 5-HT receptors, the pharmacological profiles of these receptors are markedly different.
5-HT5 receptors may be localized in the olfactory bulb, hippocampus, cortex, cerebral ventricles, corpus callosum, and cerebellum using molecular biological techniques. Immunohistochemical methods have shown that 5-HT5 receptors of neurons are expressed in various regions of the brain (Oliver et al., Brain Res. 2000, 867, 131-142; Pasqualetti et al., Mol. Brain Res. 1998, 56, 1-8). On the one hand, these 5-HT5 receptors may directly or indirectly modulate important functions of the brain, and on the other hand may also participate in mechanisms involved in neuropathological, neurodegenerative, and neuropsychiatric diseases. 5-HT5 receptors have also been localized in astrocytes (Carson et al., GLIA 17:317-326 (1996)). Astrocytes are in direct contact with the basal membrane of brain capillaries of the blood-brain barrier; an abnormal astrocyte-endothelium structure is accompanied by a loss of the blood-brain barrier. The exact function of astrocytes is not understood. Astrocytes appear to perform transport tasks and connective functions. Reactive astrocytes have been observed in conjunction with reactive gliosis for a number of pathological brain changes and neuropsychiatric diseases. Such astrocytes alter their morphology as the result of brain injuries. The protein expression pattern changes, and growth factors are produced. In vitro tests of cultivated astrocytes have shown 5-HT5 receptor-mediated responses. For this reason it is suspected that 5-HT5 receptors are involved in healing processes of the brain subsequent to disorders, but on the other hand it cannot be ruled out that they also contribute to the origin or even proliferation of damage.
Neuropathological conditions currently affect a large percentage of the population, and the number of patients is continually on the rise due to the increasing numbers of older persons.
Neuropathological conditions such as cerebral ischemia, stroke, epilepsy, and attacks in general, chronic schizophrenia, other psychotic conditions, depression, anxiety, bipolar disorders, dementia, in particular Alzheimer's dementia, demyelinating diseases, in particular multiple sclerosis, and brain tumors result in damage to the brain and the associated neuronal deficiencies. Therapeutic treatments of the described neurodegenerative and neuropathological disorders have heretofore focused on various membrane receptors, with the objective of compensating for deficits in neurotransmission processes. It has been possible to achieve neuroprotective effects by use of various serotonergic compounds in animal models for neuropathological conditions such as ischemia, stroke, and excitotoxicity, and in some cases beneficial effects have also been observed for mood disorders such as depression or anxiety. Named here as examples are 5-HT1A agonists such as buspirone, or the compound 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) which is characterized as a selective 5-HT1A receptor ligand. However, these active substances alleviate the described neurological deficits to only a limited extent, and there is currently no effective therapy for these conditions.
Another neuropathological condition which affects large numbers of people is migraine. In most cases migraine is manifested by recurring headaches, which affect an estimated 8 million persons, namely, 3-5% of all children, 7% of all men, and 14% of all women. Although a genetic predisposition is popularly reported, the causes appear to be multifaceted (Diener H. C. et al., Arzneimitteltherapie 15:387-394 (1997)). There are two dominant hypotheses: The long-known blood vessel theory proposes that the cause is a dilation process of the internal and external cerebral vascular system. The neurogenic theory is based on a release of vasoactive neurotransmitters, primarily neuropeptides such as substance P and neurokinin, from axons of the vascular system due to stimulation of ganglia which innervate specific brain tissue, resulting in inflammatory reactions and pain.
There is currently no causal therapy for treatment of migraine. Two different treatment methods are presently in use: first, a prophylactic therapy for prevention of recurring migraine attacks, and second, symptomatic therapy for suppression of acute symptoms during attacks. Migraine-specific active substances such as Sanmigran®, Nocerton®, Desernil®, and Vidora®, as well as active substances customarily used for other indications, such as beta blockers, antiemetic active substances such as Sibelium®, antidepressive agents such as Laroxyl®, or antiepileptic active substances such as Depakin® are administered for preventative treatment. Administered within the scope of acute therapy are analgesics such as aspirin, paracetamol, or Optalidon®, nonsteroidal anti-inflammatory agents such as Cebutid®, Voltaren®, Brufen®, Ponstyl®, Profenid®, Apranx®, and Naprosin® for pain and inflammation, ergot alkaloids such as ergotamine and dihydroergotamine, which may trigger vasoconstriction, or substances of the triptan family, such as sumatriptan, Naramig®, and AscoTop® with a high affinity for 5-HT1D receptors. The latter substances act as agonists and inhibit vasodilation.
However, the referenced active substances are not optimally suited for treatment of migraine. Nonopioid analgesics frequently have side effects. Due to the powerful peripheral vasoconstriction, the complex action mechanism of ergot alkaloids results in side effects such as hypertonia and gangrene. Compounds of the triptan family are likewise not fully satisfactory (Pfaffenrath V. Münch. Med. Wschr. 625-626 (1998).
5-HT5 receptors show a high affinity for various antidepressants and antipsychotic agents. Previous studies indicate that 5-HT5 receptors play a role in the following disease profiles:
Psychosis, depression, chronic schizophrenia, other psychotic conditions, anxiety, bipolar disorders, dementia, in particular Alzheimer's dementia, demyelinating diseases, in particular multiple sclerosis, and ischemia, stroke, and migraine.
The use of 5-HT5 receptor ligands for the general treatment of migraine and other cerebrovascular diseases is described in WO 00/041472, and for the treatment of neurodegenerative and neuropsychiatric diseases, in WO 00/041696.
Therefore, there is a need for substances which effect modulation of 5-HT5A receptor activity.